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J C Jennette

Publications and source records attributed to J C Jennette.

At least 55 records · Page 3Linked to original sources
PubMed1997

Crosslinking of ANCA-antigens stimulates superoxide release by human neutrophils.

Anti-neutrophil cytoplasmic antibodies (ANCA) activate primed human polymorphonuclear neutrophils (PMN) in vitro, resulting in a respiratory burst and degranulation. In this study, the hypotheses that the initiation of this process requires engagement of the F(ab')2 portion of ANCA, and that crosslinking of ANCA target antigens is necessary to trigger superoxide (O2-) release, were explored. It is speculated that Fc gamma receptor engagement is a modulator of ANCA-mediated activation. Flow cytometry demonstrated that intact human ANCA immunoglobulin (Ig), their corresponding F(ab')2 and Fab fragments, as well as a murine monoclonal to human PR3 and its F(ab')2 fragment, bind to ANCA antigens on the surface of PMN primed with tumor necrosis factor (TNF) alpha. Intact Ig of patients with PR3-ANCA or with MPO-ANCA stimulate O2- release from TNF alpha-primed normal PMN (2.6 +/- 3.57 to 15.3 +/- 7.39 nmol O2-/2.5 x 10(6) PMN/30 min). Corresponding F(ab')2 fragments result in similar O2- production (10.2 +/- 4.34 to 36.9 nmol) in a dose-dependent manner. ANCA Fab fragments do not stimulate O2- generation until these fragments are crosslinked with F(ab')2 of goat anti-human Ig F(ab')2, or when fragments are biotinylated and crosslinked with avidin. In contrast with these human autoantibody data, a mouse monoclonal anti-human PR3 antibody (25.7 +/- 8.55 nmol O2-), but not its corresponding F(ab')2 fragment, activates TNF alpha-treated human PMN. When the Fc gamma IIa receptors were blocked, superoxide production was reduced by 33% using human PR3-ANCA Ig (P < 0.05). In conclusion, PMN activation by ANCA occurs when intact ANCA or ANCA F(ab')2 fragments crosslink target antigens on the neutrophil cell surface. ANCA F(ab') fragments result in PMN activation when crosslinked by secondary reagents.

Animals↗
PubMed1997

Neutrophil superoxide release is required for spontaneous and FMLP-mediated but not for TNF alpha-mediated apoptosis.

Polymorphonuclear leukocyte (PMN) lifespan is characterized by both rapid production and apoptotic cell death. The mechanisms triggering apoptosis in PMN are not completely understood. In this study, the relationship of neutrophil activation and apoptosis as related to released superoxide was investigated. PMN apoptosis was detected by DNA fragmentation, and ultraviolet and light microscopy, and was quantified by flow cytometry; superoxide release was measured by superoxide dismutase-inhibitable reduction of ferricytochrome C. Incubation of PMN with 20 ng/ml tumor necrosis factor (TNF)alpha induced superoxide release (8.8 +/- 7.5 nmol O2-/30 min, n = 7) in normal PMN and also resulted in apoptosis within 2 h, whereas a subactivating dose of 2 ng/ml TNF alpha, which did not trigger superoxide release (3.1 +/- 1.7 nmol O2-, n = 10), did facilitate apoptosis, although to a lesser degree. PMN cultured under nonstimulating conditions underwent apoptotic cell death after 8 h. Exogenous superoxide dismutase did not inhibit apoptosis induced by 20 ng/ml TNF alpha. No upregulation of endogenous manganese superoxide dismutase mRNA expression was observed in response to TNF alpha as measured by reverse transcription PCR. Formyl-methionyl-leucyl-phenylalanine (FMLP) stimulation (10(-7) M) resulting in superoxide release of 31.7 +/- 6.1 nmol O2-/30 min (n = 10) also significantly increased the percentage of apoptosis, but at 24 h (P < 0.05). Exogenous superoxide dismutase did inhibit FMLP-induced apoptosis, as well as apoptosis due to aging in culture. In conclusion, aging and FMLP-stimulated PMN undergo apoptosis by a superoxide release-dependent pathway, whereas TNF alpha-facilitated apoptosis appears to be unrelated to respiratory burst oxidase activity.

Apoptosis↗
PubMed1996

Frequency of anti-bactericidal/permeability-increasing protein (BPI) and anti-azurocidin in patients with renal disease.

The major subtypes of anti-neutrophil cytoplasmic antibodies (ANCA) detected by indirect immunofluorescence assay (IFA) are P-ANCA and C-ANCA. In patients with vasculitis, myeloperoxidase (MPO) is the major P-ANCA antigen and proteinase 3 (PR3) is the major C-ANCA antigen. BPI and azurocidin, which are also called 57-kD cationic antimicrobial protein (CAP 57) and 37-kD cationic antimicrobial protein (CAP 37), respectively, have been proposed as less frequent target antigens for C-ANCA and P-ANCA. In patients with renal disease, we determined the frequency of antibodies against BPI and azurocidin. By IFA on alcohol-fixed neutrophils, monoclonal and polyclonal anti-BPI antibodies produced a C-ANCA pattern, whereas rabbit anti-azurocidin antibody produced a P-ANCA pattern. By ELISA, sera from 229 P-ANCA-positive patients, 99 C-ANCA-positive patients and 48 ANCA-negative (by IFA) patients with renal biopsies were tested for reactivity with recombinant human BPI and purified human azurocidin. Of these sera, 17.5% of P-ANCA, 30.3% of C-ANCA and 20.8% of IFA-ANCA-negative sera were positive for anti-BPI; and 8.3% of P-ANCA, 3.0% of C-ANCA and 8.3% of IFA-ANCA-negative sera were positive for anti-azurocidin. There was no statistical difference in frequency of anti-BPI between pauci-immune necrotizing and crescentic glomerulonephritis (NCGN) and other glomerular disease (OGD), and there was a lower frequency of anti-azurocidin in NCGN samples than in OGD samples. By Western blot, anti-BPI-positive sera reacted with a 57-kD BPI band and anti-azurocidin-positive sera with a 29-kD azurocidin band. In conclusion, there is a low frequency of anti-BPI and anti-azurocidin antibodies in ANCA-positive patient sera; however, this does not correlate with NCGN, which is a marker for ANCA-associated small vessel vasculitis, and a similar positivity is found in IFA-ANCA-negative patients with renal disease. Therefore, serologic detection of anti-BPI and anti-azurocidin is not diagnostically specific in patients with renal disease.

Amino Acid Sequence↗
PubMed1996

Wegener's granulomatosis mimicking a sternal abscess.

Bone destruction as a manifestation of Wegener's granulomatosis has been reported, but these cases were limited to the head and face. We present a case in which a sternal abscess was the initial manifestation of Wegener's granulomatosis. We believe this is the first reported case of bone destruction due to Wegener's occurring in a location other than the head and face.

Abscess↗
PubMed1996

Prognostic markers in patients with antineutrophil cytoplasmic autoantibody-associated microscopic polyangiitis and glomerulonephritis.

The purpose of this study was to determine the prognostic value of clinical, laboratory, and pathologic features at the time of presentation on patient and renal survival in patients with antineutrophil cytoplasmic autoantibody (ANCA)-associated microscopic polyangiitis and glomerulonephritis (excluding Wegener's granulomatosis). One hundred seven ANCA-positive patients with necrotizing and crescentic glomerulonephritis, including 69 with evidence for microscopic polyangiitis, were evaluated for this study. The relative risk of death was calculated for the following potential prognostic indicators: (1) ANCA pattern; (2) pulmonary hemorrhage at onset; (3) presence of extrarenal manifestations versus renal limited disease; and (4) treatment with corticosteroids and cyclophosphamide (intravenous or oral), compared with corticosteroids alone. Cox's proportional hazard model was used to assess the predictive value of the following variables on renal survival: (1) age; (2) race; (3) pulmonary symptoms at onset of disease; (4) renal pathology; (5) ANCA pattern; and (6) peak serum creatinine values obtained near the time of renal biopsy. Patients were followed prospectively for 2.5 yr (range, 5 days to 12 yr 2 months). There were 12 disease-related deaths and 46 patients who reached ESRD. The relative risk (and 95% confidence interval) of patient death was 8.65 (3.36, 22.2) times greater in patients who presented with pulmonary hemorrhage, and 3.78 (1.22, 11.70) times greater in patients with cytoplasmic ANCA compared to those with perinuclear ANCA. The relative risk of pulmonary hemorrhage was no different by ANCA pattern. The risk of death was 5.56 times lower in the cyclophosphamide-treated patients versus those treated with corticosteroids alone. The predictors of renal survival were entry serum creatinine value (P = 0.0002), race (African Americans having a worse outcome compared with Caucasians, P = 0.0008), and the presence of arterial sclerosis on kidney biopsy (P = 0.0076) when controlling for age, ANCA pattern, microscopic polyangiitis versus glomerulonephritis alone, and pulmonary involvement. Pathology indices such as glomerular necrosis, glomerular crescents, glomerular sclerosis, and interstitial sclerosis were not predictive of renal survival when controlling for entry serum creatinine value, race, and arterial sclerosis. However, in the subgroup of patients with a peak creatinine value of < or = 3.0 mg/dL (N = 29), increased interstitial sclerosis was a predictor of a poor renal outcome (P = 0.04).

Adolescent↗
PubMed1996

Treatment response and relapse in antineutrophil cytoplasmic autoantibody-associated microscopic polyangiitis and glomerulonephritis.

In this study, the rate of remission, relapse, and treatment resistance in 107 patients with microscopic polyangiitis and necrotizing and crescentic glomerulonephritis associated with antineutrophil cytoplasmic autoantibodies were assessed. Patients with Wegener's granulomatosis were excluded. Prospective criteria were identified to assess remission, relapse, and resistant disease. Ninety-seven of the 107 patients received treatment with corticosteroids (N = 25) or with cyclophosphamide and corticosteroids (N = 72). Of these patients, 75 (77.3%) went into remission (complete remission, N = 61; remission on therapy, N = 14). Of the 75 responders, 32 patients (43%) remained in long-term remission, for a mean follow-up of 44 +/- 29 months; 15 patients (20%) progressed to ESRD without signs of relapse, for a mean of 21.4 +/- 22.8 months after the end of treatment; 6 patients died. Twenty-two of the 75 patients who initially responded to treatment (29%) suffered a relapse that occurred within 18 months of the end of therapy and usually affected the same organ systems as on initial presentation. There was a significant difference in the remission rate between the corticosteroid-treated patients and the cyclophosphamide-treated patients (56% versus 84.7%, P = 0.003), and the cyclophosphamide-treated patients had three times less risk of experiencing a relapse than did corticosteroid-treated patients (0.31, 95% Cl = (0.12, 0.84)). Seventy-seven percent (17 of 22 patients) of treatment resistance occurred in patients who presented with fulminant disease or advanced and severe renal disease. It was concluded that most patients with microscopic polyangiitis or necrotizing and crescentic glomerulonephritis achieve remission with therapy. Relapses occur in 29% of patients and generally respond to retreatment. Initial treatment with cyclophosphamide and corticosteroids rather than corticosteroids alone results in a lower frequency of relapse. Even patients who require dialysis at presentation may benefit from treatment, however, patients who are not treated until the disease process is life-threatening may die before induction therapy is complete, indicating the continued need for early diagnosis and therapy.

Adolescent↗
PubMed1996

Shared idiotypy among patients with myeloperoxidase-anti-neutrophil cytoplasmic autoantibody associated glomerulonephritis and vasculitis.

Anti-neutrophil cytoplasmic autoantibodies (ANCA) have been hypothesized to participate in the pathogenesis of necrotizing vasculitis based on their association with small vessel vasculitides and the in vitro ability of such antibodies to activate cytokine-primed neutrophils. Much remains to be elucidated about the factors responsible for the generation and perpetuation of these autoantibodies and the shaping of the ANCA immune response. This study evaluated the clonal diversity of the ANCA immune response in patients with myeloperoxidase-ANCA associated disease. Isoelectric focusing was used to investigate the clonality of myeloperoxidase-ANCA from 34 patients with pauci-immune necrotizing glomerulonephritis. Sixty-nine percent of the patients had two or less clonotypes to myeloperoxidase, whereas 31% had more than two clonotypes. Clonality was stable over the course of the disease and shared among some unrelated patients. Shared idiotypy was specifically investigated using a murine monoclonal anti-idiotype (7F2C11) to the anti-myeloperoxidase antibodies of one patient with ANCA associated vasculitis. This monoclonal antibody was selected by demonstrating: (1) binding to the proband's affinity purified anti-myeloperoxidase antibodies; (2) an inhibitory effect on the binding of the proband's anti-myeloperoxidase to myeloperoxidase; and (3) lack of binding to control human antibody preparations, or to the proband's crude immunoglobulin preparation, thus excluding an anti-allotype antibody. Purified 7F2C11 was immobilized on Sepharose, and this monoclonal anti-idiotype affinity column was used to search for a shared anti-myeloperoxidase idiotype in the plasma of four other patients with myeloperoxidase-ANCA associated disease. Using this column, we were able to extract anti-myeloperoxidase antibodies from plasma of the other patients but not from control antibody preparations. We concluded that most myeloperoxidase-ANCA patients have a restricted response to myeloperoxidase and that some patients share a common idiotype. The demonstration of shared idiotypy suggests a restricted number of autoreactive epitopes of the myeloperoxidase molecule, or that some anti-myeloperoxidase autoantibodies are encoded by germ line genes, or both.

Animals↗
PubMed1996

Apoptosis of endothelial cells induced by the neutrophil serine proteases proteinase 3 and elastase.

The pathogenesis of vasculitis associated with anti-neutrophil cytoplasmic antibodies is not established. The anti-neutrophil cytoplasmic antibody autoanigens proteinase 3 (PR3) and elastase induce detachment and cytolysis of endothelial cells in vitro. We investigated whether PR3 and elastase trigger endothelial cell apoptosis. Primary bovine pulmonary artery endothelial cells were treated with either PR3, elastase, or myeloperoxidase (MPO) and apoptosis assessed by four different methods. By the cell death detection enzyme-linked immunosorbent assay, DNA fragmentation increased to 208 +/- 84% or 153 +/- 27% of control with 1 micrograms/ml PR3 or elastase at 24 hours. By ultraviolet light microscopy, the percentage of apoptotic cells significantly increased (P < 0.05) with 5 or 10 micrograms/ml PR3 and 25 or 50 micrograms/ml elastase at 6, 12, or 24 hours. Values at the 24-hour time point are 15.3 +/- 6.4% or 25.8 +/- 6.6% for 5 or 10 micrograms/ml PR3 and 13.9 +/- 3.6% or 20.7 +/- 1.8% for 25 or 50 micrograms/ml elastase compared with 2.2 +/- 1.2% for control. Similarly, with flow cytometry, 5 or 10 micrograms/ml PR3 and 25 or 50 micrograms/ml elastase for 6, 12, or 24 hours demonstrated increasing apoptosis in a dose- and time-dependent manner with the highest values achieved at 24 hours (23.4 +/- 4.0% and 35.6% for 5 and 10 micrograms/ml PR3 and 31.8 +/- 4.0% and 47.8% for 25 and 50 micrograms/ml elastase compared with 7.9 +/- 2.2% in control). Typical DNA laddering was apparent from 6 to 24 hours at 5 or 10 micrograms/ml PR3 and 25 or 50 micrograms/ml elastase. Myeloperoxidase did not induce cell apoptosis. Release of PR3 and elastase by activated neutrophils during acute inflammation, including anti-neutrophil cytoplasmic antibody-associated vasculitis, may result in vascular damage by endothelial cell apoptosis.

Animals↗
PubMed1995

Prostaglandin synthase 2 gene disruption causes severe renal pathology in the mouse.

The prostaglandin endoperoxide H synthase isoform 2, cyclooxygenase 2 (COX-2), is induced at high levels in migratory and other responding cells by pro-inflammatory stimuli. COX-2 is generally considered to be a mediator of inflammation. Its isoform, COX-1, is constitutively expressed in most tissues and is thought to mediate "housekeeping" functions. These two enzymes are therapeutic targets of the widely used nonsteroidal anti-inflammatory drugs (NSAIDs). To investigate further the different physiologic roles of these isoforms, we have used homologous recombination to disrupt the mouse gene encoding COX-2 (Ptgs2). Mice lacking COX-2 have normal inflammatory responses to treatments with tetradecanoyl phorbol acetate or with arachidonic acid. However, they develop severe nephropathy and are susceptible to peritonitis.

Animals↗
PubMed1995

Male-female differences in fertility and blood pressure in ACE-deficient mice.

Angiotensin-converting enzyme (ACE) is a dipeptidyl carboxy-peptidase that generates the vasoconstricting peptide angiotensin II and inactivates the vasodilating peptide bradykinin. The gene encoding ACE is composed of two homologous regions and codes for both a somatic and testis isoenzyme. Experiments with hypertensive rats and some, but not other, studies of humans suggest that sequences at or linked to the gene influence blood pressure. The testis-specific form of ACE has its own promoter within intron 12 (ref. 14), is encoded by the 3' region of the gene, and is found only in postmeiotic spermatogenic cells and sperm. Its function is unknown. Here we investigate the role of the Ace gene in blood pressure control and reproduction using mice generated to carry an insertional mutation that is designed to inactivate both forms of ACE. All homozygous female mutants were found to be fertile, but the fertility of homozygous male mutants was greatly reduced. Heterozygous males but not females had blood pressures that were 15-20 mm Hg less than normal, although both male and female heterozygotes had reduced serum ACE activity.

Animals↗
PubMed1995

Genetic control of blood pressure and the angiotensinogen locus.

Variants of the human angiotensinogen gene have been linked in some studies to increased circulating angiotensinogen levels and essential hypertension. To test for direct causality between genotypes at the angiotensinogen locus and blood pressures, we have studied mice carrying zero, one, two, three, or four functional copies of the murine wild-type angiotensinogen gene (Agt) at its normal chromosomal location. Plasma angiotensinogen levels increase progressively, although not linearly, from zero in the zero-copy animals to 145% of normal in the four-copy animals. Mice of all genotypes are normal at birth, but most zero-copy animals die before weaning. The kidneys of the zero-copy animals show pathological changes as adults, but the kidneys are normal in the other genotypes. One adult zero-copy male tested was fertile. The blood pressures of the one-copy through four-copy animals show significant and almost linear increases of approximately 8 mmHg per gene copy despite their normal compensatory mechanisms being intact. These results establish a direct causal relationship between Agt genotypes and blood pressures.

Aging↗
PubMed1995

A review of therapeutic studies of idiopathic membranous glomerulopathy.

The treatment of idiopathic membranous glomerulopathy remains an enigma. We have reviewed many of the important clinical trials concerning membranous glomerulopathy using a meta-analysis and a secondary pooled analysis to test the effects of corticosteroid or alkylating, therapy compared with no treatment on renal survival and complete remission of the nephrotic syndrome. A search was performed using MEDLINE (1968 through 1993) for articles on idiopathic membranous glomerulopathy and glomerulonephritis. Bibliographies of articles were reviewed for completeness. Sixty-nine articles were reviewed. Meta-analysis was performed for four trials that evaluated corticosteroids compared with no treatment and for three trials that evaluated alkylating therapy compared with no treatment. Pooled analysis was performed on randomized and prospective studies (10 studies) and then with 22 case series added. All studies evaluated renal biopsy-proven disease. Meta-analysis was performed on the relative chance of being in complete remission for each study. Renal survival could be evaluated by pooled analysis only. For pooled analyses, Cox's proportional hazard and logistic regression models were used to test the effect of therapy on renal survival and the nephrotic syndrome, respectively. Data concerning gender, nephrotic syndrome, and geographic region were used in all statistical models. Evaluation of renal survival revealed no differences by treatment group (P > 0.1). By meta-analysis, the relative chance of complete remission was not improved for corticosteroid-treated patients (1.55; 95% confidence interval, 0.99 to 2.44; P > 0.1), but was improved for patients treated with alkylating agents (4.8; 95% confidence interval, 1.44 to 15.96; P < 0.05) when compared with no treatment. Pooled analysis of randomized and prospective studies, as well pooled analysis with all studies, supported the findings of the meta-analysis. Corticosteroids or alkylating therapy did not improve renal survival in idiopathic membranous glomerulopathy. Complete remission of the nephrotic syndrome was observed more frequently with the use of alkylating agents.

Adolescent↗
PubMed1995

The pathologic spectrum of pulmonary lesions in patients with anti-neutrophil cytoplasmic autoantibodies specific for anti-proteinase 3 and anti-myeloperoxidase.

Anti-neutrophil cytoplasmic autoantibodies (ANCA) occur in a subset of patients with systemic small vessel vasculitis, including patients with Wegener's granulomatosis, microscopic polyangiitis (microscopic polyarteritis), and Churg-Strauss syndrome. Pulmonary disease appears at some time during the course in many patients with ANCA-associated vasculitis. The histologic features of 25 open lung biopsies and two autopsy cases were studied from 27 patients with ANCA. Patients' ages ranged from 8 to 79 years with a mean of 52.6 years. There were 12 females and 15 males. Autoantibodies were characterized as C-ANCA in 13 patients and as P-ANCA in 14 patients. Anti-proteinase 3 antibodies were documented in 12 of 13 patients with C-ANCA. Anti-myeloperoxidase antibodies were documented in all 14 patients with P-ANCA. Vascular lesions were present in 21 patients (78%) and 11 patients (41%) had bronchial lesions. Capillaritis was the most common vascular lesion (17 patients, 63%), and was found with similar frequency in patients with C-ANCA and those with P-ANCA. Extravascular structures were a common site of tissue injury. Airway lesions including bronchiolitis obliterans organizing pneumonia (4 patients, 19%), necrotizing granulomatous inflammation (4 patients, 15%), and non-granulomatous inflammation (3 patients, 11%) were more commonly associated with patients with C-ANCA. Interstitial lesions were found in 20 patients (74%), and included necrotizing granulomatous inflammation (8 patients, 30%), fibrosis (13 patients, 48%), and chronic inflammation (12 patients, 44%). No histologic lesion were found that were specific for C-ANCA or P-ANCA. This series demonstrates the wide variety of pulmonary lesions found in patients with ANCA-associated pulmonary disease, and shows that extravascular structures are a common site of injury in ANCA-associated vasculitis.

Adolescent↗
PubMed1995

Autoantibodies to topoisomerase I in a patient with systemic lupus erythematosus without features of scleroderma.

We report a woman with systemic lupus erythematosus (SLE) with diffuse proliferative glomerulonephritis and anti-dsDNA antibodies whose serum contained autoantibodies specific for the phosphorylated form of RNA polymerase II (RNAP IIO), Su and ribosomal P antigen, as well as anti-topoisomerase I antibodies, a marker for scleroderma (SSc). Over 6 years, the patient exhibited clinical manifestations consistent with SLE without clinical evidence of scleroderma. The reactivity of her serum autoantibodies with the phosphoproteins ribosomal P, topoisomerase I, and RNAP IIO is consistent with recognition of autoepitopes comprised in part of phosphate groups. This may explain the unexpected coexistence of marker autoantibodies for SLE and scleroderma, possibly with implications for the mechanisms of autoantibody generation.

Adult↗
PubMed1995

Antimyeloperoxidase antibodies induce neutrophil adherence to cultured human endothelial cells.

Antimyeloperoxidase autoantibodies are found in the sera of some patients with glomerulonephritis and systemic vasculitis. Previously, we demonstrated that they were able to stimulate neutrophils to damage cultured human endothelial cells. We now report that antimyeloperoxidase antibodies are able to stimulate neutrophils to adhere to cultured human endothelial cells. Immunoglobulin G purified from myeloperoxidase-antineutrophil cytoplasmic autoantibody positive sera increased adherence to 331 +/- 60% of unstimulated controls. In a similar manner, rabbit antimyeloperoxidase enhanced neutrophil adherence. Stimulating the endothelial cells with 10 micrograms/mL endotoxin enhanced antimyeloperoxidase stimulated adherence. In the presence of a CD18 blocking antibody (MoAb 60.3), antimyeloperoxidase-stimulated adherence was significantly decreased. These results add further understanding to the antimyeloperoxidase-stimulated neutrophil-endothelial cell interaction and further support the hypothesis that antimyeloperoxidase autoantibodies are of pathogenic import in glomerulonephritis and vasculitis.

Analysis of Variance↗